Withdrawal versus continuation of chronic antipsychotic drugs for behavioural and psychological symptoms in older people with dementia (Review)

Transcription

1 Withdrawal versus continuation of chronic antipsychotic drugs for behavioural and psychological symptoms in older people with Declercq T, Petrovic M, Azermai M, Vander Stichele R, De Sutter AIM, van Driel ML, Christiaens T This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2013, Issue 3

2 T A B L E O F C O N T E N T S HEADER ABSTRACT PLAIN LANGUAGE SUMMARY BACKGROUND OBJECTIVES METHODS RESULTS Figure Figure Figure DISCUSSION AUTHORS CONCLUSIONS ACKNOWLEDGEMENTS REFERENCES CHARACTERISTICS OF STUDIES DATA AND ANALYSES Analysis 1.1. Comparison 1 Discontinuation versus continuation of antipsychotic medication: continuous data, analysis method mean difference, Outcome 1 Behavioural assessment by using NPI measuring NPS at 3 months (Ballard 2004 and Ballard DART-AD) (forest plot 1) ADDITIONAL TABLES APPENDICES CONTRIBUTIONS OF AUTHORS DECLARATIONS OF INTEREST SOURCES OF SUPPORT DIFFERENCES BETWEEN PROTOCOL AND REVIEW i

3 [Intervention Review] Withdrawal versus continuation of chronic antipsychotic drugs for behavioural and psychological symptoms in older people with dementia Tom Declercq 1, Mirko Petrovic 2, Majda Azermai 3, Robert Vander Stichele 4, An IM De Sutter 1, Mieke L van Driel 5, Thierry Christiaens 1 1 Department of General Practice and Primary Health Care, Ghent University, Ghent, Belgium. 2 Department of Geriatrics, Ghent University Hospital, Ghent, Belgium. 3 Heymans Institute of Clinical Pharmacology, Ghent University, Ghent, Belgium. 4 Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium. 5 Discipline of General Practice, School of Medicine, The University of Queensland, Brisbane, Australia Contact address: Tom Declercq, Department of General Practice and Primary Health Care, Ghent University, De Pintelaan 185, UZ- 6K3, Ghent, B-9000, Belgium. tomrw.declercq@ugent.be. Editorial group: Cochrane Dementia and Cognitive Improvement Group. Publication status and date: New, published in Issue 3, Review content assessed as up-to-date: 6 December Citation: Declercq T, Petrovic M, Azermai M, Vander Stichele R, De Sutter AIM, van Driel ML, Christiaens T. Withdrawal versus continuation of chronic antipsychotic drugs for behavioural and psychological symptoms in older people with dementia. Cochrane Database of Systematic Reviews 2013, Issue 3. Art. No.: CD DOI: / CD pub2. Background A B S T R A C T Antipsychotic agents are often used to treat neuropsychiatric symptoms (NPS) in dementia, although the literature is sceptical about their long-term use for this indication. Their effectiveness is limited and there is concern about adverse effects, including higher mortality with long-term use. When behavioural strategies have failed and drug therapy is instituted, regular attempts to withdraw these drugs are recommended. Physicians, nurses and families of older people with dementia are often reluctant to try to stop antipsychotics, fearing deterioration of NPS. Strategies to reduce antipsychotic use have been proposed, but a systematic review of interventions aimed at withdrawal of antipsychotic agents in older people with dementia has not yet been performed. Objectives To evaluate whether withdrawal of antipsychotic agents is successful in older people with dementia in community or nursing home settings, to list the different strategies for withdrawal of antipsychotic agents in older people with dementia and NPS, and to measure the effects of withdrawal of antipsychotic agents on behaviour. Search methods ALOIS, the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (CDCIG), The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS, clinical trials registries and grey literature sources were searched on 23 November The search included the following terms: antipsychotic* or neuroleptic* or phenothiazines or butyrophenones or risperidone or olanzapine or haloperidol or prothipendyl or methotrimeprazine or clopenthixol or flupenthixol or clothiapine or metylperon or droperidol or pipamperone or benperidol or bromperidol or fluspirilene or pimozide or penfluridol or sulpiride or veralipride or levosulpiride or sultopride or aripiprazole or clozapine or quetiapine or thioridazine combined wither terms such as discontinu* or withdraw* or cessat* or reduce* or reducing or reduct* or taper* or stop*. 1

4 ALOIS contains records from all major healthcare databases (The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS), as well as from many clinical trials registries and grey literature sources. Selection criteria Randomised, placebo-controlled trials comparing an antipsychotic withdrawal strategy to continuation of antipsychotics in people with dementia. Data collection and analysis Review authors independently assessed trials for inclusion, rated their risk of bias and extracted data. Main results We included nine trials with 606 randomised participants. Seven trials were conducted in nursing homes, one trial in an outpatient setting and one in both settings. In these trials, different types of antipsychotics prescribed at different doses were withdrawn. Both abrupt and gradual withdrawal schedules were used. The risk of bias of the included studies was generally low regarding blinding and outcome reporting and unclear for randomisation procedures and recruitment of participants. There was a wide variety of outcome measures. Our primary efficacy outcomes were success of withdrawal (i.e. remaining in study off antipsychotics) and NPS. Eight of nine trials reported no overall significant difference between groups on the primary outcomes, although in one pilot study of people with psychosis and agitation that had responded to haloperidol, time to relapse was significantly shorter in the discontinuation group (Chi 2 = 4.1, P value = 0.04). The ninth trial included people with psychosis or agitation who had responded well to risperidone therapy for four to eight months and reported that discontinuation led to an increased risk of relapse, that is, increase in the Neuropsychiatric Inventory (NPI)-core score of 30% or greater (P value = 0.004, hazard ratio (HR) 1.94, 95% confidence interval (CI) 1.09 to 3.45 at four months). The only outcome that could be pooled was the full NPI-score, used in two studies. For this outcome there was no significant difference between people withdrawn from and those continuing on antipsychotics at three months (mean difference (MD) -1.49, 95% CI to 2.40). These two studies reported subgroup analyses according to baseline NPI-score (14 or less versus > 14). In one study, those with milder symptoms at baseline were significantly less agitated at three months in the discontinuation group (NPI-agitation, Mann-Whitney U test z = 2.4, P value = 0.018). In both studies, there was evidence of significant behavioural deterioration in people with more severe baseline NPS who were withdrawn from antipsychotics (Chi 2 = 6.8; P value = for the marked symptom score in one study). Individual studies did not report significant differences between groups on any other outcome except one trial that found a significant difference in a measure of verbal fluency, favouring discontinuation. Most trials lacked power to detect clinically important differences between groups. Adverse events were not systematically assessed. In one trial there was a non-significant increase in mortality in people who continued antipsychotic treatment (5% to 8% greater than placebo, depending on the population analysed, measured at 12 months). This trend became significant three years after randomisation, but due to dropout and uncertainty about the use of antipsychotics in this followup period this result should be interpreted with caution. Authors conclusions Our findings suggest that many older people with Alzheimer s dementia and NPS can be withdrawn from chronic antipsychotic medication without detrimental effects on their behaviour. It remains uncertain whether withdrawal is beneficial for cognition or psychomotor status, but the results of this review suggest that discontinuation programmes could be incorporated into routine practice. However, two studies of people whose agitation or psychosis had previously responded well to antipsychotic treatment found an increased risk of relapse or shorter time to relapse after discontinuation. Two other studies suggest that people with more severe NPS at baseline could benefit from continuing their antipsychotic medication. In these people, withdrawal might not be recommended. P L A I N L A N G U A G E S U M M A R Y Withdrawal of chronic antipsychotic drugs for behavioural and psychological symptoms in older people with dementia People with dementia often have behavioural problems that can be difficult for carers to manage. Antipsychotic drugs are often prescribed to control symptoms and assist with controlling difficult behaviour. Many people with dementia continue to take these drugs over long periods of time. This review investigates whether withdrawal of long-term antipsychotic treatment is feasible in older 2

5 people with dementia suffering from behavioural symptoms (often called neuropsychiatric symptoms or NPS). These include agitation, aggression, hallucinations, anxiety, apathy, depression, delusions (beliefs that cannot be true), wandering, repeating of words or sounds, and shouting. Nine studies with 606 participants provided data for the review. Most of the participants were residents in nursing homes, but some were outpatients. The studies differed considerably in participants, methods and outcomes so that is was not possible to combine most of the data numerically. The evidence suggests that older nursing home residents or outpatients with dementia can be withdrawn from long-term antipsychotics without detrimental effects on their behaviour. Caution is required in older nursing home residents with more severe NPS, as two studies suggest these peoples symptoms might be worse if their antipsychotic medication is withdrawn. Moreover, one study suggested that older people with dementia and psychosis or agitation and a good response to their antipsychotic treatment for several months could relapse after discontinuation of their antipsychotic medication. We do not know if there are beneficial effects of withdrawal on intellectual processes, quality of life or ability to carry out daily tasks, or if the risk of harmful events is reduced by drug withdrawal. One study suggests that older people with dementia who continue to take antipsychotics might die earlier. We recommend that programmes that aim to withdraw older nursing home residents from long-term antipsychotics should be incorporated into routine clinical practice, especially if the NPS are not severe. More research is needed to identify people for whom withdrawal is not indicated and risk of relapse should be weighed against the risk of adverse events with long-term antipsychotic treatment. B A C K G R O U N D Description of the condition According to the World Health Organization (WHO), the need for healthcare services for older people with dementia will increase significantly over the next 10 years (Ferri 2005). Up to 50% of older individuals aged 85 years and above have dementia, with Alzheimer s dementia (AD), vascular dementia and dementia with Lewy bodies being the most frequent diagnoses. Although cognitive deficits are the clinical hallmark of dementia, non-cognitive symptoms are common and can dominate the disease presentation. These symptoms include a wide range of neuropsychiatric symptoms (NPS), such as agitation, aggression, hallucinations, anxiety, apathy, depression, delusions, wandering, repetitive vocalisations, shouting, and many other symptoms. These NPS have been observed in 60% to 98% of people with dementia, especially in later stages of the disease. Prevalences of each type of NPS vary considerably, from 3% to 54% for delusions, 1% to 39% for hallucinations, 8% to 74% for depressed mood, 7% to 69% for anxiety, 17% to 84% for apathy, 48% to 82% for aggression or agitation, and 11% to 44% for physical aggression (Zuidema 2007). There are several clusters of NPS according to the dominant symptom and different clusters have been described. Petrovic reports four behavioural syndromes: a cluster with predominantly psychotic symptoms (hallucinations, irritability, agitation and anxiety); a cluster with predominantly mood disorders (disinhibition, elation and depressive symptoms); a cluster with predominantly psychomotor symptoms (aberrant motor behaviour) and a cluster with predominantly instinctual symptoms (appetite disturbance, sleep disturbance and apathy) (Petrovic 2007). Each cluster could reflect a different prevalence, course over time, biological correlate, psychosocial determinant and treatment, but there probably is overlap between different clusters. In the US the cluster with predominantly psychotic symptoms, including hallucinations and delusions, is considered to be robust enough for the Food and Drug Administration (FDA) to recognise it as an indication for drug treatment (Ballard 2006). NPS lead to carer stress and depression and can cause considerable emotional discomfort. In people with dementia, NPS are associated with higher mortality, use of physical restraints, increased length of hospitalisation, and often precipitate admission into a nursing home (Gilley 2000). Up to 30% of the costs of caring for people with dementia are directly attributed to the management of NPS (Herrmann 2006). Therefore, interventions aimed at treating NPS could have an important impact on people with dementia, carers and society (Sink 2005). Although multiple classes of drugs, including antipsychotic or neuroleptic agents, are used to treat NPS, there is no strong evidence to support the choice of drugs for different clusters of NPS. NPS have a fluctuating nature and high placebo response rates have been reported. Furthermore, most trials investigating the efficacy of drug treatment are only short-term. Therefore, treatment is often based on expert opinion, consensus guidelines or local prescribing habits (Finkel 1996; IPA 2003). An individual tailored approach may offer more and better non-pharmacological and pharmacological treatment opportunities (Robert 2005). Numerous authors (Ballard 2010; Gauthier 2010), as well as good practice guidelines (NICE 2006), suggest that non-pharmacolog- 3

6 ical treatment of NPS in people with dementia should be the first choice. Clinical trials show non-pharmacological treatments, such as psychological and training interventions, are effective in reducing NPS in people with dementia (Deudon 2009). The effect of pharmacological dementia treatments on NPS has been studied in different trials. A review of the effect of cholinesterase inhibitors on NPS in dementia concluded that the evidence is equivocal and unconvincing (Sink 2005). Although some suggest cholinesterase inhibitors may be useful for symptoms, such as apathy and psychosis, initial reports that these medications may reduce agitation were not confirmed by a large non-industry-funded randomised controlled trial (RCT) (Howard 2007). Post-hoc analysis of trials of memantine, a N-methyl D- aspartate antagonist, suggests a potential effect on agitation and aggression (Gauthier 2005). Ongoing RCTs in Canada and in the UK will hopefully clarify the role of memantine in the treatment of agitation/aggression in AD and vascular dementia (Ballard 2010). Evidence for other drugs, such as carbamazepine and antidepressants in managing behavioural and psychological symptoms of dementia, is very limited. The use of benzodiazepines in the treatment of NPS in older people with dementia is not evidence based and should be discouraged because of the risk of dependence and falls (CADTH 2010). There is also evidence that atypical or second-generation antipsychotic agents can effectively treat agitation, aggression or psychotic symptoms when non-pharmacological, that is, behavioural, interventions have failed (Ballard 2006). A major concern of antipsychotic treatment for behavioural symptoms in people with dementia is the increased risk of mortality and stroke (Schneider 2005; Schneider 2006). Product side effect and hazard warnings have been issued for atypical antipsychotics (FDA 2005; FDA 2008), and also for the older typical or firstgeneration antipsychotics in the treatment of psychotic symptoms in older people with dementia. Meanwhile in the UK, Banerjee concluded it was time for action in his report to the Minister of State (Banerjee 2009). His review of the literature of antipsychotic treatment in older people with dementia revealed that while improvement in behavioural disturbance was minimal after 6 to 12 weeks of treatment (estimated effect size 0.1 to 0.2), there was a significant increase in absolute mortality risk of approximately 1% (Banerjee 2009). As the literature suggests that prescribing of antipsychotics in dementia continues beyond 6 to 12 weeks, the harm of continued antipsychotic treatment in dementia is likely to be substantial. Moreover, Huybrechts and co-workers report that in their population cohort study the risk of mortality in people taking antipsychotics is generally increased with higher doses and seems to be different for each molecule (in their study it was highest for haloperidol) (Huybrechts 2012). In spite of this evidence, antipsychotic agents remain widely used as the first-line management of NPS in people with dementia (Briesacher 2005). According to a retrospective analysis in the US, approximately 27.6% of all Medicare beneficiaries in nursing homes received at least one prescription for antipsychotic drugs during 2000 to Most of the atypical antipsychotics were not prescribed in accordance with guidelines and the administered doses and indications were not supported by strong clinical evidence. In 2001, antipsychotics were ranked highest on the list of expenditure for Medicaid programmes, the main provider of medications prescribed in nursing homes in the US (Briesacher 2005). Unlike the US, other countries do not have legislation on the use of chemical restraints for people with dementia and NPS. In a survey of medication use in Belgian nursing homes, the list of health insurance drug expenditure is headed by antipsychotics, antithrombotic agents and antidepressants. In terms of health costs, antipsychotics are the second largest group of prescribed drugs in older people living in Belgian nursing homes. Most frequently prescribed are atypical antipsychotics, with risperidone and olanzapine at the top of the list (Azermai 2011; Vander Stichele 2006). Considering the lack of efficacy in chronic use coupled with concerns for safety and high health expenditure, the use of antipsychotics for individuals in nursing homes should be limited in time (O Brien 2008). In the UK, Banerjee recommended using antipsychotics only when they really need it and more attention should go to training and non-pharmacological interventions (Banerjee 2009). Withdrawal seems a rational management option when the person has stabilised. Data on the clinical effect of antipsychotic withdrawal remain limited and antipsychotic withdrawal symptoms/syndrome, although rare, can be very severe (Mortimer 2005). However, Ballard has shown that withdrawal from antipsychotics can be safe in people with dementia who have taken antipsychotics for prolonged periods, especially when symptoms have largely resolved (Ballard 2008). Description of the intervention Withdrawal from antipsychotic agents can be either abrupt (immediate cessation of the active medication) or tapered (gradual withdrawal according to a predefined dosing schedule or following clinical response). In this review, we assemble and appraise RCTs investigating interventions aimed at assisting older people with dementia to withdraw from antipsychotics, either by stopping abruptly or by tapering. How the intervention might work Withdrawal of antipsychotic agents in older people, often frail, people with dementia and NPS might theoretically improve cognitive function, quality of life (QoL) for people with dementia and carers, and decrease mortality and adverse events (e.g. falls and extrapyramidal symptoms). However, drug withdrawal might also cause a recurrence or worsening of the original NPS with a 4

7 negative impact on the QoL for people with dementia and their carers and it might cause a temporary withdrawal syndrome. Why it is important to do this review Carers looking after people who are agitated and taking drugs that may be suppressing such symptoms, are sometimes understandably reluctant to consider withdrawal of the drug. However, the episodic nature of such symptoms and the harms associated with antipsychotic use is less well appreciated. A systematic review of the risks and benefits of antipsychotic withdrawal and of the feasibility of maintaining people off antipsychotics is therefore needed. O B J E C T I V E S To evaluate whether withdrawal of antipsychotic agents is feasible in older people with dementia and NPS in primary care or nursing home settings; to list the different strategies for withdrawal of antipsychotic agents in older people with dementia and NPS; and to measure the effects of the withdrawal of antipsychotic agents on peoples behaviour and assess safety issues such as mortality, adverse effects or withdrawal symptoms. M E T H O D S Criteria for considering studies for this review Types of studies All relevant RCTs. Withdrawal trials that were not placebo-controlled were only included if the outcome assessors were blinded. No language restrictions were applied. Types of participants Older people with dementia under primary care or living in nursing homes and taking an antipsychotic drug. Older people are defined as 65 years or older without age limit. Dementia is defined as an acquired organic mental disorder with loss of intellectual abilities of sufficient severity to interfere with social or occupational functioning. The dysfunction is multifaceted and involves memory, behaviour, personality, judgment, attention, spatial relations, language, abstract thought, and other executive functions. The intellectual decline is usually progressive, and initially spares the level of consciousness. We accepted studies for inclusion if the reports stated that participants had dementia or any subtype of dementia. If there was any doubt about this diagnosis, first authors were asked to provide further information. All grades of dementia severity were included. People with schizophrenia were excluded if this was reported in the trial. By accepting all types and grades of dementia severity, regardless of the method of diagnosis, we are reflecting the current situation in practice in which many demented residents in nursing homes are not formally diagnosed. We believe this way of including people will make the review as widely applicable as possible. Nursing homes are defined as institutions in which long-term care is provided by professional care workers for three or more unrelated, frail, older individuals. Types of interventions Withdrawal of antipsychotic drugs prescribed chronically for behavioural and NPS in older people with dementia. Chronic use is defined as use of at least three months of any antipsychotic agent, either typical (first generation) or atypical (second generation) at a fixed dosage. Although there is no good definition of the subgroup of atypical antipsychotic drugs, we prefer this term above new or second-generation antipsychotics. The antipsychotic agents are listed according to the Anatomical Therapeutic Chemical (ATC) classification. Names of drug classes are listed in Table 1, names of individual drug are listed in Table 2, and atypical antipsychotic agents are labelled with an asterisk. The antipsychotic agent should be used in a stable dose, and within the therapeutic range as mentioned in the attached drug information insert. Defined daily doses (per os) as mentioned in the ATC classification are also listed in Table 2. Chlorpromazine is considered the reference drug. Baseline dosage regimen is classified as very low, low or high for each antipsychotic agent, according to the dosage table proposed by Ballard in Ballard The DART-AD Trial (e.g. for risperidone a dose of 0.5 mg once daily is very low, 0.5 mg twice daily is low and 1 mg twice daily is high; for haloperidol 0.75 mg once daily is very low, 0.75 mg twice daily is low and 1.5 mg twice daily is high; for the referent molecule chlorpromazine 12.5 mg once daily is very low, 12.5 mg twice daily is low and 25 mg twice daily is high). Types of outcome measures Primary outcomes 1.1. Success of withdrawal from antipsychotics over short-term (four weeks or less) and long-term (more than four weeks) followup. Success rate is defined as the ability to complete the study, that is, no dropout of the trial due to worsening of NPS, or no relapse to antipsychotic drug use during the trial Behavioural and psychological symptoms (especially agitation, aggression and psychotic symptoms) of people continuing on antipsychotics versus people withdrawn from antipsychotics measured with appropriate scales (e.g. Neuropsychiatric Inventory (NPI) score, Neuropsychiatric Inventory Questionnaire score (NPI-Q) score), and compared to baseline. 5

8 1.3. Presence or absence of withdrawal symptoms or withdrawal syndrome in people withdrawn from antipsychotics in the first four weeks after withdrawal. Withdrawal symptoms or withdrawal syndrome include autonomic and behavioural symptoms such as nausea, vomiting, anorexia, rhinorrhoea, diarrhoea, diaphoresis, myalgia, paraesthesia, anxiety, as well as movement disorders, such as withdrawal emergent parkinsonism, withdrawal dyskinesia and covert dyskinesia. Agitation, insomnia and restlessness have also been reported during withdrawal, although it is possible that these symptoms occur due to rebound phenomenon. It is impossible to discriminate between these two aetiological phenomena. A withdrawal neuroleptic malignant syndrome is a very rare but extremely severe condition that can complicate abrupt antipsychotic discontinuation Adverse events of antipsychotics (e.g. falls, extrapyramidal symptoms using the Extrapyramidal Symptom Rating Scale (ESRS), cardiovascular events and diabetes) in people withdrawn from antipsychotics versus people continuing antipsychotics. Secondary outcomes 2.1. Cognitive function (e.g. short-term memory) of people continuing on antipsychotics versus people withdrawn from antipsychotics measured with appropriate scales (Severe Impairment Battery (SIB) score, Standardised Mini-Mental State Examination (SMMSE)) and compared to baseline QoL of participants, carers, families, or a combination continuing on antipsychotics versus people withdrawn from antipsychotics measured with appropriate scales (e.g. Dementia Care Mapping) and compared to baseline Time, in days, until repeat prescription of any psychotropic or any antipsychotic agent in people withdrawn from antipsychotics versus people continuing on antipsychotics Use of physical restraint in people withdrawn from antipsychotics versus people continuing on antipsychotics compared with baseline Mortality in people withdrawn from antipsychotics versus people continuing on antipsychotics Other secondary outcomes (e.g. global functioning, sleep or language) measured with appropriate scales and compared to baseline. Search methods for identification of studies Electronic searches We searched ALOIS ( the Cochrane Dementia and Cognitive Improvement Group s Specialized Register, on 9 February 2009 (initial search), 11 March 2011 (updated search) and 1 June and 23 November (pre-publication searches). After external review, we did a supplementary search of additional antipsychotics not covered in previous searches in August and November 2012 (supplementary searches). ALOIS is maintained by the Trials Search Co-ordinator of the Dementia Group and contains studies in the areas of dementia prevention, dementia treatment and cognitive enhancement in healthy. The studies are identified from: 1. monthly searches of a number of major healthcare databases: MEDLINE, EMBASE, CINAHL, PsycINFO and LILACs; 2. monthly searches of a number of trial registers: ISRCTN; UMIN (Japan s Trial Register); the WHO portal (which covers ClinicalTrials.gov; ISRCTN; the Chinese Clinical Trials Register; the German Clinical Trials Register; the Iranian Registry of Clinical Trials and the Netherlands National Trials Register, plus others); 3. quarterly search of The Cochrane Library s Central Register of Controlled Trials (CENTRAL); 4. six-monthly searches of a number of grey literature sources: ISI Web of Knowledge Conference Proceedings; Index to Theses; Australasian Digital Theses. To view a list of all sources searched for ALOIS see About ALOIS on the ALOIS website. Details of the search strategies used for the retrieval of reports of trials from the healthcare databases, CENTRAL and conference proceedings can be viewed in the methods used in reviews section within the editorial information about the Dementia and Cognitive Improvement Group. Additional searches were performed in many of the sources listed above to cover the timeframe from the last searches performed for ALOIS to ensure that the search for the review was as up to date and as comprehensive as possible. The search strategies used can be seen in Appendix 1, Appendix 2 and Appendix 3. Appendix 4 gives a full list of abbreviations used in this review. Data collection and analysis Selection of studies 1. Searches and screening of the identified studies were performed independently by two review authors (TD and MP). 2. All trials were scrutinised for relevance and pre-defined inclusion criteria. Trials that did not fulfil the criteria were excluded. 3. Differences between review authors were resolved by consensus and by consulting a third review author (TC). Data extraction and management 6

9 Data extraction was performed by two independent review authors (TD, MA). Disagreement was resolved by an external expert (Ellen De Schepper, biomedical statistician). The summary statistics required for each trial and outcome for continuous data are the mean change from baseline, the standard error of the mean change, and the number of participants for each treatment group at each assessment. The baseline assessment is defined as the latest available assessment prior to randomisation, but no longer than two weeks before randomisation. Where changes from baseline were not reported, the mean, standard deviation (SD), and the number of people in each treatment group at each time point were extracted if available. For binary data, the number in each treatment group and the numbers experiencing the outcome of interest were sought. The outcomes measured in dementia trials often arise from ordinal rating scales. Where ordinal rating scales used in the trials had a reasonable large number of categories (more than 10), the data were treated as continuous outcomes arising from a normal distribution, where necessary using a Turnstone Transformation. For each outcome measure, data were sought on every person assessed. To allow an intention-to-treat (ITT) analysis, the data were sought irrespective of compliance, whether or not the person was subsequently deemed ineligible, or otherwise excluded from treatment or follow-up. If ITT data were not available in the publications, on-treatment, or the data of those who completed the trial were sought and indicated as such. When studies included an open period after the main comparative phase, data from non-randomised follow-on periods were not used. Additional data and characteristics of the participants extracted from the individual studies were listed as co-variables: withdrawal method (e.g. abruptly versus tapered withdrawal); baseline severity of NPS (e.g. NPI-score), agitation (e.g. Cohen-Mansfield Agitation Inventory (CMAI) scale), or psychotic symptoms (hallucinations, delusions); baseline severity of dementia as determined by the MMSE score (e.g. mild: 19 to 16; moderate: 15 to 10; severe: 9 to untestable), or other appropriate scales; baseline dose of antipsychotic agent (very low, low, high) and type of antipsychotic agents (typical or atypical); sex of participant; age of participant by age groups (years): 65 to 69; 70 to 79; 80 to 89; 90 and older. Assessment of risk of bias in included studies The risk of bias in each of the trials was assessed by using the following criteria of internal validity: randomisation (sequence allocation), allocation concealment, blinding of participant and outcome assessor, adequate reporting of and dealing with withdrawals and dropouts, selective outcome reporting and other risks of bias. The guidelines in the Cochrane Handbook for Systematic Reviews of Interventions were used (Higgins 2011). Two review authors (TD, MA) independently assessed the risk of bias of the included studies. Disagreement was resolved by consulting with two other review authors (MP, TC). Measures of treatment effect Meta-analysis requires the combination of data from trials that may not use the same rating scale to assess an outcome. The measure of the treatment difference for any continuous outcome is the weighted mean difference when the pooled trials use the same rating scale or test. The standardised mean difference, which is the absolute mean difference divided by the pooled SD, was calculated when different rating scales or tests were used. For binary outcomes, such as improvement or no improvement, the odds ratio was used to measure treatment effect. Peto odds ratios were calculated using RevMan 5 Software (RevMan 2011). 95% Confidence intervals were calculated for each of the pooled estimates. Unit of analysis issues We considered whether in each study, groups of individuals were randomised together (in clusters) to the same intervention, whether individuals underwent more than one intervention, or whether there were multiple observations for the same outcome. Dealing with missing data We describe if data were missing from the published report. We contacted the original investigators to request missing data. If these data remained unavailable we analysed the available data using an ITT analysis. Any statistical method used by the study authors (e.g. multiple imputation analysis, last observation carried forward) to deal with not-missing-at-random data is reported. If study authors reported outcomes for participants who completed the study, as well as carried forward or otherwise imputed data, we used the latter data for pooling. Assessment of heterogeneity Studies were analysed and presented separately. Meta-analysis was only performed when studies were sufficiently homogeneous in terms of participants, interventions and outcomes. Both clinical (face value) heterogeneity and statistical heterogeneity were considered, the latter by means of a Higgins I 2 test. An I 2 value of 50% or higher was considered as significant heterogeneity. 7

10 Assessment of reporting biases In order to minimise the risk of publication bias, a comprehensive search was performed in multiple databases, including searching for unpublished studies. The existence of publication bias was not explored by means of a graphical funnel plot analysis as an insufficient number of studies was available (< 10 studies). Data synthesis If trials were considered too clinically heterogeneous at face value the results were not pooled in meta-analysis. The duration of follow-up in trials varied considerably. If the range of follow-up was considered too large to pool results into one meta-analysis, the data were divided into smaller time periods and a separate meta-analysis was conducted for each period. Some trials contributed data to more than one time period if multiple assessments were made. The overall estimate was calculated using a fixed-effect model in the absence of statistical heterogeneity. In the presence of substantial statistical heterogeneity, a random-effects model was used (Higgins 2011). Data are reported in the table of comparisons. A complete list of outcomes can be found in the table of comparisons. Further analyses included examination of dropout rates. Subgroup analysis and investigation of heterogeneity Subgroup analyses were performed for relevant and clinically meaningful subgroups when sufficient data were available (i.e. more than one study), such as type of intervention, severity of dementia or NPS, setting, gender of participant and type of antipsychotic agent. Sensitivity analysis When evidence of small study effects was found, authors considered sensitivity analyses according to Copas examining how the results of the possible meta-analysis change under different assumptions relating to the reasons for these effects (Higgins 2011). R E S U L T S Description of studies See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of ongoing studies. Nine studies met the inclusion criteria. The characteristics of all included studies are described in detail in the Characteristics of included studies tables. Results of the search From the 529 hits found in 17 different databases through the initial electronic search from 9 February 2009, 309 references of published studies and four references of ongoing studies were retrieved. After screening (by TD and MP), 22 references of published studies were selected as potentially eligible. These were found to refer to seven unique studies. Bridges-Parlet 1996 was retrieved as a dissertation that was subsequently published as Bridges-Parlet 1997; Cohen-Mansfield 1996 was the conference proceedings of Cohen-Mansfield 1999; and Ballard 2000, Ballard 2003b, Fossey and Ballard 2000 and Ballard 2006 were all references related to the registration of Ballard Another reference (Onyike 2008) was a comment on Ballard The DART-AD Trial and was therefore not considered for inclusion. Findlay 1989 was identified from reference lists as the seventh study eligible for inclusion. One potentially relevant to date unpublished study (Engedal) was also identified and added to the list of ongoing studies to be included in future updates of this review (Appendix 1; Appendix 2). The updated search of 11 March 2011 retrieved 776 hits of which the review authors (TD and MP) assessed 70 thoroughly. No new trials were identified for inclusion or exclusion. The pre-publication search of 1 June 2012 retrieved 454 hits of which 11 were further assessed: the review authors (TD and MP) identified one new pilot study for the ongoing Devanand ADAD- Trial, which was included in this review (Devanand 2011). In addition, in April 2012 the study design of the Devanand ADAD 2012 was published and this reference added to the other references section. The search of 13 August 2012 revealed one additional study that was potentially eligible for inclusion (Horwitz 1995). However this study was not a clinical trial and therefore was excluded. In November 2012, the second pre-publication search revealed 19 new hits, from which one study was identified and included (the Devanand ADAD 2012 trial). Included studies Two review authors (TD, MP) independently selected nine different trials from 11 papers: they found two papers reporting the Ballard The DART-AD Trial and one paper (Ruths 2004) reporting a subgroup analysis of Ruths The BEDNURS Study. The included trials were very different regarding study participants (such as the case definition applied and the severity of dementia of the participants), types and dosages of antipsychotics used before withdrawal, exclusion criteria, interventions (i.e. method of withdrawal), outcomes and time of assessment. Only two studies (Ballard The DART-AD Trial; Ballard 2004) used the same main outcome (i.e. the NPI -score), and provided sufficient information to allow pooling of data. Ruths The BEDNURS Study used the NPI-Q as main outcome, which is a short version of the NPI. Devanand ADAD 2012 reported relapse defined as an increase in the NPI core score (i.e. the sum of the sub-scales for agita- 8

11 tion-aggression, hallucinations, and delusions on the NPI-score), and a score of 1 (very much improved) or 2 (much improved) on the Clinical Global Impression of Change (CGI-C) scale for overall psychosis or agitation. Therefore data of these two trials (Devanand ADAD 2012; Ruths The BEDNURS Study) could not be pooled with data of the former two Ballard trials. The authors of Bridges-Parlet 1997, Cohen-Mansfield 1999, Findlay 1989 and van Reekum 2002 responded that they were unable to provide additional data. Setting Seven studies include people in nursing homes. One pilot study included outpatients with AD and psychosis, agitation or aggression (Devanand 2011). Devanand ADAD 2012 included outpatients or residents of assisted-living facilities or nursing homes with AD and psychosis, agitation, or aggression. Case definition of dementia All studies used different methods (e.g. Diagnostic and Statistical Manual of Mental Disorders - 3rd Edition Revised (DSM IIIR), Diagnostic and Statistical Manual of Mental Disorders - 4th Edition (DSM IV)) to diagnose dementia, including AD. Ballard 2004 and Ballard The DART-AD Trial included only people with AD that fulfilled the National Institute of Neurological and Communicative Diseases and Stroke/ Alzheimer s Disease and Related Disorders Association (NINCDS-ADRDA) criteria for possible or probable AD. Bridges-Parlet 1997 included residents with a diagnosis of dementia and subjects with a history of physical aggressive behaviour (PAB) according to the nursing home staff. Cohen-Mansfield 1999 had no explicit diagnostic standard for dementia because the study included nursing home residents older than 70 years receiving haloperidol, thioridazine and lorazepam. The first author confirmed by that the residents participating in her study met the inclusion criteria for this review (suffering from dementia). Devanand 2011 included outpatients with probable AD using the DSM-IV and National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer s Disease and Related Disorders Association (NINCDS-ADRDA) criteria. Devanand ADAD 2012 included outpatients or residents of assisted-living facilities or nursing homes who met the criteria for dementia using the DSM-IV, and the criteria for probable AD of the NINCDS-ADRDA. Findlay 1989 included exclusively women with AD in accordance with the International Classification of Diseases (ICD)-9 criteria, assessed by a consultant psychiatrist and based on the medical history. van Reekum 2002 included people with all forms of dementia based on chart review. Ruths and co-workers included people with a dementia diagnosis according to the clinical criteria of ICD, 10th Revision (Ruths The BEDNURS Study). Severity of dementia In three studies, participants were described as having mild-tomoderate or severe dementia, based on MMSE scores. In the Ballard 2004 study participants had a Clinical Dementia Rating (CDR) Scale severity of stage 1 or greater. Participants in the Ballard The DART-AD Trial had either an MMSE score > 6 or a Severe Battery Impairment score > 30. Ruths The BEDNURS Study included all participants regardless individual symptoms (absent = 0, mild = 1, moderate = 2, severe = 3), providing a NPI-Q sum score ranging from 0 to 36. In the other studies, no clear cut-off values were reported to indicate the difference in degree/severity of dementia. However, assessment of cognitive status occurred in most studies using the MMSE. Bridges-Parlet 1997 did not report the severity of dementia. At baseline cognitive status was assessed using the MMSE. Participants were selected by nurse supervisors who identified physically aggressive people with dementia treated with antipsychotics. In the study by Cohen-Mansfield 1999, the Brief Cognitive Rating Scale (BCRS) was used at baseline to determine participants stage of dementia, to characterise the study population and to stratify groups according to cognitive function (1 to 3 versus 4 to 7 on the BCRS). In the Devanand 2011 pilot trial the eligible MMSE score was 5 to 26. Participants also needed to have signs of psychosis or agitation, or both, to be included in the study. Psychosis was identified by the Columbia University Scale for Psychopathology in Alzheimer s Disease (CUSPAD) and the Brief Psychiatric Rating Scale (BPRS) (psychosis factor of at least 4). Agitation was measured on the Consortium to Establish a Registry for Alzheimer s Disease (CERAD) Behavioural Rating Scale for Dementia (score of greater than 3 and present at least 10 days per month, on one or more of the items for agitation, purposeless wandering, verbal aggression or physical aggression). Participants in the Devanand ADAD 2012 had a score of 5 to 26 on the MMSE in the case of outpatients and a score of 2 to 26 in the case of nursing home residents. In addition participants had a score on the NPI of 4 or more at both screening and baseline on the delusions or hallucinations sub-scale (psychosis score) or the agitation-aggression sub-scale (agitation score). The study of Findlay 1989 was limited to AD without further specification. Antipsychotic treatments to be withdrawn 9

12 All studies used different antipsychotics in different dosages. Antipsychotics used were thioridazine, chlorpromazine, haloperidol, trifluoperazine (classified as typical antipsychotics ) and risperidone or olanzapine (classified as atypical antipsychotics ). Antipsychotic dosage varied across the studies. Three studies used an abrupt withdrawal schedule (Ballard 2004; Ballard The DART-AD Trial; Ruths The BEDNURS Study). Two studies (Bridges-Parlet 1997; Devanand ADAD 2012) withdrew most participants abruptly from antipsychotic drugs, but tapering still occurred when the baseline dose exceeded the equivalent of 50 mg of chlorpromazine by dropping the baseline antipsychotic dose in half during week one and discontinuing the antipsychotic agent completely at the beginning of week two (Bridges-Parlet 1997) or when the baseline dose was 2 mg risperidone or more daily by oneweek tapering by means of a sequential double-blind placebo substitution (e.g. one 2-mg tablet of risperidone was switched to one 1-mg tablet and then to one placebo tablet) (Devanand ADAD 2012).The other studies used a tapering schedule. In the Ballard The DART-AD Trial, a majority of participants were taking risperidone or haloperidol at variable dosages: participants were taking at least 10-mg chlorpromazine equivalents (CPZe) of a typical neuroleptic or at least 0.5 mg daily of risperidone. Dosages were defined as high versus low versus very low: very low: risperidone 0.5 mg daily, chlorpromazine 12.5 mg once daily, trifluoperazine 0.5 mg once daily; haloperidol 0.75 mg once daily; low: risperidone 0.5 mg twice daily, chlorpromazine 12.5 mg twice daily, trifluoperazine 0.5 mg twice daily; haloperidol 0.75 mg twice daily; and high: risperidone 1 mg twice daily; chlorpromazine 25 mg twice daily; trifluoperazine 1 mg twice daily; haloperidol 1.5 mg twice daily. In Ballard 2004, a majority of participants took risperidone or thioridazine at variable dosages. Participants used (mean ± SD dose): risperidone 1.3 mg ± 0.7 mg, thioridazine 38.0 mg ± 26.2 mg, haloperidol 0.9 mg ± 0.4 mg, trifluoperazine 3.0 mg ± 1.4 mg or chlorpromazine 20 mg (no SD value for chlorpromazine as there was only one person taking this drug). In Cohen-Mansfield 1999, participants were taking haloperidol, thioridazine and lorazepam at variable dosages (mean dosage haloperidol 1.34 mg, thioridazine 27.0 mg and lorazepam 0.94 mg, no SD given). The cross-over design of this trial led to a three-week dose-tapering period followed by seven weeks of placebo period. After this placebo period, the placebo group was titrated back to the original dose and groups were switched for the procedure. Participants were withdrawn from both antipsychotics (haloperidol and thioridazine), and lorazepam, which is a benzodiazepine. Because of this dual drug cross-over design, it will be difficult to interpret the results of this study. In Devanand 2011, outpatients with AD and symptoms of psychosis or agitation were included and treated with haloperidol in phase A. In phase B (discontinuation trial) only participants who responded well to haloperidol in phase A were included. Criteria for clinical response were minimum 50% reduction from baseline in the sum score of the three most prominent symptoms of psychosis or agitation, a sum score of 6 or less on these three items (range 0 to 18), and minimal or greater improvement on the CGI-C score (rated only for symptoms of psychosis or agitation). Doses of haloperidol used in phase B varied (4 mg daily, 2 to 3 mg daily, 0.5 to 1 mg daily). According to these different dosages there was a two-week tapering period (4 mg daily switched to 2 mg daily for one week, 1 mg daily for the next week and then to placebo; participants on 2 to 3 mg daily switched to 1 mg daily for two weeks and then to placebo, and participants who received 0.5 or 1 mg daily were switched directly to placebo without a tapering period). In the Devanand ADAD 2012, phase A participants were given flexible-dose risperidone for 16 weeks: risperidone therapy was initiated at a dose of 0.25 to 0.5 mg daily and could be increased to 3 mg daily, depending on the response and side effects. Participants who had a response in phase A entered phase B of the study (discontinuation trial with three regimens: continued risperidone therapy for 32 weeks (group 1), risperidone therapy for 16 weeks followed by placebo for 16 weeks (group 2) or placebo for 32 weeks (group 3). Findlay 1989 used a half-dose reduction during the first week and a total placebo substitution over the next week. Original dosages that participants had been receiving were stable dosages between 10 and 100 mg thioridazine for at least two months. van Reekum 2002 did not define antipsychotic drug classes and included residents that used typical or atypical antipsychotics for at least six months. In this study, all subjects received a standard order for lorazepam (0.5 to 1.0 mg) on an asneeded basis for agitation. The study used a tapering schedule of two weeks in which original medication was halved for the first week and the remaining dose halved during the second week followed by a six-month study period. In Ruths The BEDNURS Study, participants were taking risperidone 1.0 mg (median; range 0.5 to 2.0 mg), olanzapine 5.0 mg (2.5 to 5.0 mg), and haloperidol 1.0 mg (0.5 to 1.5 mg). Excluded participants See Characteristics of included studies table. Outcome measurements Outcome measures were very different across included studies and therefore difficult to compare. Ballard 2004, Ballard The DART-AD Trial and Ruths The BEDNURS Study reported outcomes in mean differences with SDs. Bridges-Parlet 1997, 10

13 Cohen-Mansfield 1999, Devanand 2011, Devanand ADAD 2012 and van Reekum 2002 reported outcomes as means, but only Bridges-Parlet 1997, Devanand 2011 and Devanand ADAD 2012 reported SDs as well. Findlay 1989 reported outcomes as means with a range (number of observations). 1. Primary outcomes 1.1. Success of withdrawal from antipsychotics in the short term (four weeks or less) and long term (more than four weeks) Success rate is defined as ability to complete the study (i.e. no withdrawal due to worsening of NPS, or no relapse to antipsychotic drug use during the trial). Ballard 2004 and Ballard The DART-AD Trial reported participant flow in the Results section, giving reason of withdrawal from the study, for example, withdrawal because of behavioural deterioration. Unfortunately relapse to antipsychotic drug use was not mentioned. Bridges-Parlet 1997 reported subjects completing the study and relapse to antipsychotic drug use after completion of the trial (long term). Cohen-Mansfield 1999 reported participant flow in the Results section, giving reasons why participants discontinued in the study before completion. Devanand 2011: phase B reported relapse using criteria of 50% worsening of the three target symptoms of psychosis and aggression, and a severity score 6 on these three items (range 0 to 18), and minimal or greater worsening on the CGI-C (rated for psychosis and agitation). Time to relapse was also measured in Devanand 2011 phase B. Devanand ADAD 2012: phase B reported relapse using criteria of increase in the NPI core score of 30% or more, or a 5- point increase from the score at the end of phase A, and a score of 6 (much worse) or 7 (very much worse) on the CGI-C scale. The NPI-core score is the sum of the sub-scale scores for agitationaggression, hallucinations and delusions. The CGI-C scale ranged from 1 to 7, with higher scores indicating less improvement for overall psychosis or agitation. Findlay 1989 did not report withdrawals from the study in the text, but results can be extracted from the table. van Reekum 2002 reported early withdrawals from the study, but did not mention relapse to antipsychotic drugs. Ruths The BEDNURS Study mentioned relapses of antipsychotic drug use after withdrawal from antipsychotics Behavioural and psychological symptoms measured with appropriate scales Neuropsychiatric Inventory (NPI) Scale The NPI covers 12 domains of behavioural and neurovegetative symptoms to assess outcome. Each sub-score is rated on a 12-point scale, assessing severity (0 to 3) and frequency (0 to 4) of a domain, with a theoretical maximum of 144 (i.e. 12 x 12) (range 1 to 144).The NPI score has been established to be a useful instrument for characterising the psychopathology of dementia syndromes, investigating the neurobiology of brain disorders with neuropsychiatric manifestations, distinguishing among different dementia syndromes and assessing the efficacy of treatment. The total NPI score is the major primary outcome of this review and is the only one that can be pooled because all other outcome measures were only reported in individual studies The NPI-Q (Neuropsychiatric Inventory Questionnaire) assesses only the severity of each of the same 12 domains of the NPI (theoretically maximum of 36, range 0 to 36) and can be considered as a shorter version of the NPI. Nevertheless, by assessing a spectrum of various symptoms, the NPI or NPI-Q score is not specifically evaluating the cluster with predominantly psychotic symptoms (hallucinations, irritability, agitation and anxiety). Two trials using the NPI or NPI-Q score as a primary outcome performed NPI-sub-score analysis, for example assessing agitation (Ruths The BEDNURS Study assessed agitation as a sub-score of the NPI-Q and Ballard 2004 assessed agitation as a sub-score of NPI total score). Only one trial Devanand ADAD 2012 reported the effect on the NPI core score, that is, the sum of the sub-scale NPI scores for agitation-aggression, hallucinations, and delusions, which are symptoms believed to be part of a cluster with significant clinical importance. Two studies that used the NPI-score to assess NPS will be pooled (Ballard 2004; Ballard The DART-AD Trial). The van Reekum 2002 study could not be pooled because it used the NPI as outcome measure, but unfortunately did not report this outcome in the paper. Data from Ruths The BEDNURS Study could not be pooled either because NPI-Q was used as outcome Other scales that assess behavioural and psychological symptoms Bridges-Parlet 1997 used PAB as main outcome measure. The PAB scale assesses aggressive behaviour identified by type (coded by a bar-code system). Five different types of behaviour were identified: hitting, biting, scratching, kicking and pushing. Verbal aggressiveness was defined as an instance of speaking in an angry tone of voice, swearing or yelling in anger. Bridges-Parlet 1997 also assessed verbal aggressiveness, defined as an instance of speaking in an angry tone of voice, swearing or yelling in anger. Cohen-Mansfield 1999 used behaviour and agitation measured by different scales as primary outcome: BPRS assesses somatic concern, anxiety, emotional withdrawal, conceptual disorganisation, guilt feelings, tension, mannerisms and posturing, grandiosity, depressive mood, hostility, suspiciousness, hallucinatory behaviour, motor retardation, uncooperativeness, unusual thought content, and blunted effect (scale 1 = not present to 7 = extremely severe). 11

14 Agitation was measured with the CMAI. This nurses rating questionnaire consists of 29 agitated behaviours, each rated on a 7-point scale of frequency. van Reekum 2002 used behavioural, cognitive, functional and extrapyramidal signs as outcome measures, but reported the BEHAVE-AD (Behavioural Pathology in Alzheimer s disease Rating Scale) measurements only in a figure (no means or SDs reported). Aggression was assessed by the ROAS (Retrospective Overt Aggression scale) but scores were not reported. symptoms developing during treatment, as assessed with the use of the TESS (ranges from 0 to 26, with higher scores indicating more somatic symptoms). Findlay 1989 provided some additional information on blood pressure, heart rate, mobility, and balance and sensory measures. van Reekum 2002 assessed extrapyramidal signs using ESRS, but does not report these outcomes in the paper. 2. Secondary outcomes 1.3. Presence or absence of withdrawal symptoms None of the studies assessed these specific outcomes although it is not easy to distinguish between a withdrawal phenomenon and a relapse of NPS Adverse events Adverse events related to antipsychotic use, such as falls, extrapyramidal symptoms, cognitive dysfunction, metabolic changes (including weight gain and diabetes), cardiovascular events and other are not systematically reported in the included studies. Ballard The DART-AD Trial measured parkinsonism using the M-UPDRS (Modified Unified Parkinson s Disease Rating Scale). Bridges-Parlet 1997 gave some attention to the observations of tardive dyskinesia but no measurement scales were used. The entire study was based on direct observations by experienced personnel who were blinded to the assigned treatment. Cohen-Mansfield 1999 reported adverse events as secondary outcomes in a table (without reporting an SD), using the Abnormal Involuntary Movement Scale (AIMS): assessment of neurological and physical side effects associated with psychotropic medication (nine items: e.g. movement of the face and the oral cavity, of the extremities and trunk, global judgements of abnormal movements). A list of adverse effects (sedation, extrapyramidal reactions, orthostatic hypotension and anticholinergic effects) was provided to the nursing staff, who indicated frequency of occurrence. Nurse managers checked lists of psychomotor adverse effects, including 13 items describing pseudoparkinsonism, akathisia, acute dystonic reaction and tardive dyskinesia. Devanand 2011 assessed somatic side effects by the Treatment Emergent Symptom Scale (TESS), extrapyramidal signs by the Unified Parkinson s Disease Rating Scale (UPDRS) and tardive dyskinesia by the Rockland TD scale. Devanand ADAD 2012 assessed extrapyramidal signs using the Simpson-Angus scale (ranges from 0 to 40, with higher scores indicating more extrapyramidal signs); tardive dyskinesia, with the use of the AIMS (ranges from 0 to 35, with higher scores indicating more severe symptoms) and general somatic 2.1. Cognitive function assessed by appropriate scales In the Ballard The DART-AD Trial, cognition was measured using the SMMSE and the SIB, which was the main outcome in this trial. Cohen-Mansfield 1999 assessed cognitive functioning using the MMSE scale. Devanand 2011 and Devanand ADAD 2012 also assessed cognitive functioning using the MMSE (Devanand 2011). Devanand ADAD 2012 also used the Alzheimer s Disease Assessment Scale (ADAS)-cognitive score (ranges from 0 to 70, with higher scores indicating worse cognition). Findlay 1989 used mixed cognitive/behavioural outcome measures assessed by different scales: the Cognitive Assessment Scale (CAS) scored by a psychiatrist, and a psychiatric assessment using the Sandoz Clinical Assessment Geriatric Scale (SCAGS), and the London Psychogeriatric Rating Scale (LPRS) score. van Reekum 2002 assessed cognitive outcome with the MMSE and the Mattis Dementia Rating Scale (MDRS), but did not report these outcomes in the paper Quality of life (QoL) of participants, carers, family of participants, or combination Only Ballard 2004 scored QoL using the Dementia Care Mapping (DCM) as a measure of well-being of participants Time, in days, until repeat prescription of any psychotropic agent with exception of antipsychotics was not reported systematically Only Ruths The BEDNURS Study reported medication changes in a subgroup analysis Use of physical restraint Only Bridges-Parlet 1997 reported use of physical restraint. 12

15 2.5. Mortality Ballard The DART-AD Trial and Devanand ADAD 2012 were the only studies reporting mortality. Mortality data in one of the two Ballard The DART-AD Trial papers were assessed at 12, 24 and 36 months follow-up after randomisation (outcome data analysed by ITT-analysis or mitt-analysis). Devanand ADAD 2012 assessed mortality at 16 weeks (four months) and 32 weeks (eight months) Other secondary outcomes Global functioning Ballard The DART-AD Trial reported global functioning with the BADLS (Bristol Activities of Daily Living Scale), FAST (Functional Assessment Staging) and CGI-C scales. Cohen-Mansfield 1999 reported resident functioning and global impressions of functioning as secondary outcomes using different scales, such as the CGI-C scale. Devanand 2011 assessed impairment in activities of daily living using the modified Blessed Functional Activity Scale (BFAS). Devanand ADAD 2012 assessed physical function with the use of the Physical Self-Maintenance Scale (PSMS; ranges from 1 to 30, with higher scores indicating worse functioning). van Reekum 2002 assessed functional outcome with the Blessed Dementia Scale (BDS), but did not report these outcomes in the paper Frontal executive function In the Ballard The DART-AD Trial, frontal executive function was measured by the FAS verbal fluency test, assessing phonemic verbal fluency Sleep Ruths The BEDNURS Study (sub-study Ruths 2004) and Bridges-Parlet 1997 reported the effect on sleep. Cohen-Mansfield 1999 reported the effect on sleep and activity level ratings (daytime sleep, time to fall asleep and activity level) Language Ballard The DART-AD Trial reported language by using different scales (Sheffield Test for Acquired Language Disorder (STALD receptive and STALD expressive skill)). Time of assessment of outcome measurements Most outcomes are assessed in different studies at different times and therefore difficult to pool. Ballard 2004 assessed outcomes at three months. Ballard The DART-AD Trial assessed outcomes in a first paper at 1, 3, 6 and 12 months: only the data assessed at six months were reported. In a second paper Ballard assessed the outcome mortality at 12, 24 and 36 months (outcome data analysed by ITT analysis). In order to pool the NPI score in a correct way we asked Clive Ballard to provide data from the DART-AD study assessed at three months. These data were extracted from the DART-AD database by Ly-Mee Yu from the Oxford Centre for Statistics in Medicine. Bridges-Parlet 1997 reported outcomes at one, two and four weeks. Cohen-Mansfield 1999 reported outcomes at four times of assessment: one week after start of dosage tapering (week one), phase 1 tapering (week three), phase 1 end point (week 10), phase 2 tapering (week 13), and phase 2 end point (week 20). Devanand 2011 assessed outcomes in phase B at 0, 2, 4, 8, 12, 16, 20 and 24 weeks. Devanand ADAD 2012: phase B assessed outcomes at 16 weeks (four months) and 32 weeks (eight months). Findlay 1989 reported outcomes at two and four weeks. Ruths The BEDNURS Study assessed outcomes at four weeks (one month). van Reekum 2002 reported outcomes only in a figure from visit 1 (baseline) to visit 15 (six months). Excluded studies One trial (McLennan 1992) was excluded because it analysed the Findlay 1989 cohort for outcomes that are not relevant to our review. Another study was excluded as it seems to be the registration of a not (yet) published (and perhaps still ongoing) trial and further searching did not reveal additional information about this trial (Rule 2003). Horwitz 1995, Wessels 2010 and Westbury 2011 were excluded because these were not randomised controlled discontinuation trials. 3. Co-variables Only Ballard The DART-AD Trial conducted a post hoc sub-analysis per type of antipsychotic drug (i.e. typical versus atypical). Risk of bias in included studies See Risk of bias table and summary of Risk of bias graph (Figure 1; Figure 2). 13

16 Figure 1. Risk of bias graph for the 8 included studies. 14